Millions of Americans are victims of traumatic brain injury (TBI) every year, making it a serious health challenge. TBI often involves significant axonal injury with attendant neuronal deafferentation and synaptic loss. While the brain has an inherent capacity for synaptic reorganization, this plasticity often fails after TBI, resulting in serious functional deficits. We have recently examined the role of extracellular matrix (ECM) proteins during reactive synaptogenesis induced by TBI. Our results showed that certain ECM proteins and their regulatory matrix metalloproteinases (MMPs) strongly influence the extent of recovery achieved after TBI. In these studies we contrasted ECM/MMP response in a recovering adaptive injury (unilateral entortiinal cortical lesion or DEC) and a non-recovering maladaptive insult (fluid percussion TBI + bilateral entorhinal cortical lesion orTBI+BEC). Two gelatinases (MMPs 2,9), stromelysin-1 (MMP 3) and the MMP activator plasmin all showed shifts in expression and function which correlated with different phases of reactive synaptogenesis. We also found that aberrant MMP activation was associated with failed plasticity after TBI+BEC. When MMP inhibitors were applied, plasticity was altered either positively or negatively depending upon time of dosing and complexity of injury. Given these results, we now posit that specific matrix enzyme/substrate/effector groups mediate the different phases of pre and postsynaptic recovery, as well as the subsequent stabilization of nascent synapses after injury. By contrasting the different profiles of these matrix proteins following adaptive UEC and maladaptive TBI+BEC, we will determine if individual protein dysfunction at specific phases of synaptogenesis can account for the variable extent of recovery. We will test the facilitative role of MMP3/agrin/FGF over the initial axonal sprouting phase of synaptic recovery, plasmin/phosphacan/(3-catenin during the subsequent synaptogenic period, and MT-5MMP/Ncadherin/ a-catenin at synapse stabilization. In each case we will document protein and mRNA expression, distribution in the synapse microenvironment and binding interactions. Finally, we will manipulate MMPS, plasmin or MT-5MMP in vivo by either pharmacological inhibition or siRNA knockdown and test for effect on recovery using structural and physiological indices of synaptic plasticity. These studies will better define matrix enzyme and substrate role in TBI-induced synaptic plasticity and provide new treatment strategies.